GIST
Conditions
Keywords
Other Relapsed or Refractory Solid Tumors, BLU-285, BLU 285, BLUE-285, BLUE 285, Avapritinib, GIST imatinib relapse, GIST gleevec relapse, GIST KIT, GIST relapse, GIST refractory, GIST imatinib intolerance, GIST TKI treatment, GIST tyrosine kinase inhibitor treatment, GIST TKI, GIST tyrosine kinase inhibitor, Advanced GIST, GIST mutations, GIST treatments, Blueprint GIST, Relapsed GIST clinical trial, Refractory GIST clinical trial, KIT-mutant GIST, cancer gist, gastrointestinal stromal tumor, gist cancer, PDGFRA
Brief summary
This is an open-label, randomized, Phase 3 study in patients with locally advanced unresectable or metastatic GIST (advanced GIST) of avapritinib (also known as BLU-285) versus regorafenib in patients previously treated with imatinib and 1 or 2 other TKIs.
Interventions
DRUGavapritinib
Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously.
DRUGregorafenib
Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off).
Sponsors
Blueprint Medicines Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Patients who are ≥ 18 years of age. 2. Patients who have histologically confirmed metastatic or unresectable GIST. 3. Patients who received imatinib and 1 or 2 other TKIs as prior treatment regimens. Patients who experienced intolerance to prior therapies must have objective disease progression prior to enrollment onto BLU-285-1303 study. 4. Patients who have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 to 1.
Exclusion criteria
1. Patients who have received prior treatment with avapritinib or regorafenib. 2. Patients who have previously received more than 3 different TKI treatment regimens. 3. Patients who are known to be both V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor alpha (PDGRFα) wild type. 4. Patients who received any systemic anticancer therapy within 1 week before the first dose of study drug. 5. Patients who have clinically significant cardiovascular disease 6. Patients have experienced arterial thrombotic or embolic events within 6 months before the first dose of study drug, or venous thrombotic events within 14 days of the first dose of study drug 7. Patients who have experienced any hemorrhage or bleeding event NCI CTCAE version 5.0 Grade 3 or higher within 4 weeks before the first dose of study drug 8. Patients who have a known risk of intracranial bleeding, or a history of intracranial bleeding within 1 year prior to the first dose of study drug 9. Patients who have a symptomatic non-healing wound, ulcer, gastrointestinal perforation, or bone fracture. 10. Patients who have poor organ function as defined by laboratory parameters specified in the protocol. 11. Patients who have received neutrophil growth factor support within 14 days of first dose of study drug. 12. Patients who require therapy with a concomitant medication that is a strong inhibitor or strong inducer of CYP3A4. 13. Patients who have had a major surgical procedure within 14 days of the first dose of study drug. Patient has significant traumatic injury within 28 days before the first dose of study drug. 14. Patients who have a history of another primary malignancy that has been diagnosed or required therapy within 3 years before first dose of study drug. 15. Patients who have a history of a seizure disorder requiring anti-seizure medication. 16. Patients who have metastases to the brain. 17. Patients who have a QT interval corrected using Fridericia's formula (QTcF) of \> 450 msec. 18. Women who are unwilling, if not postmenopausal or surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of the first dose of study drug and for at least 60 days after the last dose of study drug. Men who are unwilling, if not surgically sterile, to abstain from sexual intercourse or employ highly effective contraception from the time of the first dose of study drug and for at least 90 days after the last dose of study drug. 19. Women who are pregnant. 20. Women who are breastfeeding. 21. Patients who have prior or ongoing clinically significant illness, medical condition, surgical history, physical finding, or laboratory abnormality as determined by the investigator.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of Avapritinib Based on Progression-free Survival (PFS) Determined by Central Radiological Assessment Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST), Version 1.1 | 24 Months | To demonstrate the efficacy of avapritinib based on progression-free survival (PFS) determined by central radiological assessment per modified Response Evaluation Criteria in Solid Tumors (mRECIST), version 1.1 in patients with advanced GIST following 2 or 3 regimens of prior treatment with a tyrosine kinase inhibitor (TKI), including imatinib, compared to patients treated with regorafenib. A progressively growing tumor must meet the following criteria: a) the target lesions must be greater or equal to 2cm in size and be a new GIST active lesion or b) the target lesions must be expanding on at least 2 sequential imaging studies. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1 | 24 Months | To evaluate objective response rate (ORR) determined by central radiology assessment per mRECIST, version 1.1 in patients with advanced GIST treated with avapritinib compared to patients treated with regorafenib. A complete response (CR) per modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) is defined as complete disappearance of all target lesions. A partial response (PR) is defined as at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Overall Response (OR) = CR + PR |
| Overall Survival (OS) in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib | 24 Months | To evaluate overall survival (OS) in patients with advanced GIST treated with avapritinib compared to patients treated with regorafenib |
| European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30). Change in Individual Scores in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib | Difference between baseline and week 12 of treatment | The Global Health Status Score is derived from question 29 and 30 on the EORTC-QLQ-C30 tool. The change in score was assessed between baseline and week 12 in patients treated with advanced GIST treated with avapritinib compared to patients treated with regorafenib. The Global Health Status Score score range is 0 to 100 with a higher score indicating better global health status. A positive change indicates improvement in global health status. |
Countries
Australia, Austria, Belgium, Canada, China, Czechia, France, Germany, Hungary, Italy, Netherlands, Poland, Singapore, South Korea, Spain, Sweden, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Avapritinib 300 mg PO QD avapritinib: Avapritinib tablets for oral administration. Avapritinib will be dosed at 300 mg once daily, continuously. | 240 |
| Regorafinib 160 mg PO QD regorafenib: Regorafenib tablets for oral administration. Regorafenib will be dosed at 160 mg once daily for 3 weeks out of every 4 weeks (ie. 3 weeks on/1 week off). | 236 |
| Total | 476 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Administrative/Other | 33 | 32 |
| Overall Study | Death | 89 | 87 |
| Overall Study | Lost to Follow-up | 5 | 3 |
| Overall Study | Not treated | 1 | 2 |
| Overall Study | Sponsor decision | 91 | 98 |
| Overall Study | Withdrawal by Subject | 21 | 14 |
Baseline characteristics
| Characteristic | Avapritinib | Total | Regorafinib |
|---|---|---|---|
| Age, Continuous | 61.1 years STANDARD_DEVIATION 10.96 | 61.1 years STANDARD_DEVIATION 10.84 | 61.0 years STANDARD_DEVIATION 10.74 |
| Body Mass Index (BMI) | 25.50 kilogram per meter square STANDARD_DEVIATION 5.563 | 25.10 kilogram per meter square STANDARD_DEVIATION 5.378 | 24.69 kilogram per meter square STANDARD_DEVIATION 5.163 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 64 Participants | 128 Participants | 64 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 14 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 27 Participants | 50 Participants | 23 Participants |
| Race (NIH/OMB) White | 139 Participants | 282 Participants | 143 Participants |
| Region of Enrollment Australia | 5 participants | 10 participants | 5 participants |
| Region of Enrollment Austria | 0 participants | 1 participants | 1 participants |
| Region of Enrollment Belgium | 1 participants | 2 participants | 1 participants |
| Region of Enrollment Canada | 2 participants | 8 participants | 6 participants |
| Region of Enrollment China | 35 participants | 74 participants | 39 participants |
| Region of Enrollment Czechia | 3 participants | 4 participants | 1 participants |
| Region of Enrollment France | 22 participants | 42 participants | 20 participants |
| Region of Enrollment Germany | 17 participants | 35 participants | 18 participants |
| Region of Enrollment Hungary | 2 participants | 3 participants | 1 participants |
| Region of Enrollment Italy | 13 participants | 28 participants | 15 participants |
| Region of Enrollment Netherlands | 2 participants | 8 participants | 6 participants |
| Region of Enrollment Poland | 10 participants | 19 participants | 9 participants |
| Region of Enrollment Singapore | 2 participants | 4 participants | 2 participants |
| Region of Enrollment South Korea | 23 participants | 43 participants | 20 participants |
| Region of Enrollment Spain | 14 participants | 25 participants | 11 participants |
| Region of Enrollment Sweden | 6 participants | 13 participants | 7 participants |
| Region of Enrollment United Kingdom | 12 participants | 24 participants | 12 participants |
| Region of Enrollment United States | 71 participants | 133 participants | 62 participants |
| Sex: Female, Male Female | 78 Participants | 158 Participants | 80 Participants |
| Sex: Female, Male Male | 162 Participants | 318 Participants | 156 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 89 / 239 | 87 / 234 |
| other Total, other adverse events | 218 / 239 | 224 / 234 |
| serious Total, serious adverse events | 106 / 239 | 91 / 234 |
Outcome results
Primary
Efficacy of Avapritinib Based on Progression-free Survival (PFS) Determined by Central Radiological Assessment Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST), Version 1.1
To demonstrate the efficacy of avapritinib based on progression-free survival (PFS) determined by central radiological assessment per modified Response Evaluation Criteria in Solid Tumors (mRECIST), version 1.1 in patients with advanced GIST following 2 or 3 regimens of prior treatment with a tyrosine kinase inhibitor (TKI), including imatinib, compared to patients treated with regorafenib. A progressively growing tumor must meet the following criteria: a) the target lesions must be greater or equal to 2cm in size and be a new GIST active lesion or b) the target lesions must be expanding on at least 2 sequential imaging studies.
Time frame: 24 Months
Population: Intent-to-Treat Population that included all patients randomized to study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avapritinib | Efficacy of Avapritinib Based on Progression-free Survival (PFS) Determined by Central Radiological Assessment Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST), Version 1.1 | 4.2 months |
| Regorafinib | Efficacy of Avapritinib Based on Progression-free Survival (PFS) Determined by Central Radiological Assessment Per Modified Response Evaluation Criteria in Solid Tumors (mRECIST), Version 1.1 | 5.6 months |
Secondary
European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30). Change in Individual Scores in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib
The Global Health Status Score is derived from question 29 and 30 on the EORTC-QLQ-C30 tool. The change in score was assessed between baseline and week 12 in patients treated with advanced GIST treated with avapritinib compared to patients treated with regorafenib. The Global Health Status Score score range is 0 to 100 with a higher score indicating better global health status. A positive change indicates improvement in global health status.
Time frame: Difference between baseline and week 12 of treatment
Population: Intent-to-Treat Population with both a baseline and a Week 12 measurements.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Avapritinib | European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30). Change in Individual Scores in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib | -5.7 scores on a scale | Standard Deviation 24.29 |
| Regorafinib | European Organisation for Research and Treatment of Cancer Quality of Life (EORTC-QLQ-30). Change in Individual Scores in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib | -4.4 scores on a scale | Standard Deviation 20.74 |
Secondary
Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1
To evaluate objective response rate (ORR) determined by central radiology assessment per mRECIST, version 1.1 in patients with advanced GIST treated with avapritinib compared to patients treated with regorafenib. A complete response (CR) per modified Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) is defined as complete disappearance of all target lesions. A partial response (PR) is defined as at least 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum of diameters. Overall Response (OR) = CR + PR
Time frame: 24 Months
Population: Intent-to-Treat Population that included all patients randomized to study.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Avapritinib | Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1 | Responder | 41 Participants |
| Avapritinib | Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1 | Non-Responder | 199 Participants |
| Regorafinib | Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1 | Responder | 17 Participants |
| Regorafinib | Objective Response Rate (ORR) Determined by Central Radiology Assessment Per mRECIST, Version 1.1 | Non-Responder | 219 Participants |
Secondary
Overall Survival (OS) in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib
To evaluate overall survival (OS) in patients with advanced GIST treated with avapritinib compared to patients treated with regorafenib
Time frame: 24 Months
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Avapritinib | Overall Survival (OS) in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib | 19.2 months |
| Regorafinib | Overall Survival (OS) in Patients With Advanced GIST Treated With Avapritinib Compared to Patients Treated With Regorafenib | 17.4 months |